Herpes Simplex Virus (HSV) is the most widely spread virus in the herpes family. It has been identified as the pathogenic agent in a number of infectious processes involving the mucocutaneous tissues, the nervous central system, and in severe cases, the viscera. About one billion people worldwide have been infected with herpes viruses that belong to two types according to the antigenic differences in the envelope proteins: HSV type 1 (HSV-1) and HSV type 2 (HSV-2). The largest reservoir of HSV is associated with herpes labialis, most commonly resulting from primary infection with HSV-1 during childhood. The prevalence of HSV-1 and HSV-2 is estimated to be between 50-95% and 6-50% respectively, depending on several factors such as age, race, sex, marital and social status. HSV-1 primarily causes oral infections, whereas HSV-2 is the most common cause for genital ulcers.
Herpes labialis (also known as “orofacial herpes”, “orolabial herpes”, “cold sores” or “fever blisters”) is the most common recurrent infection caused by HSV-1 with considerable incidence (85% of the world's population is seropositive for HSV-1). In many cases, it causes blisters or sores on or around the mouth that are commonly known as cold sores or fever blisters. Hence, it is aesthetically unpleasant and induces considerable discomfort to the patient. Sores associated with herpes labialis typically heal within 2-3 weeks, but the virus that causes them is not removed from the body. Recurrent episodes of herpes labialis are frequent. That means that the infected herpes virus becomes dormant in the facial nerves, following orofacial infection, periodically reactivating to create sores in the same area of the mouth or face that the original infection occurred.
It is estimated that about 20-40% of people have experienced orofacial herpes at some time. In Europe, the overall incidence is approximately 3 per 1000 people per year and more than 10 per 1000 people per year in those aged over 80 years. In the United States, approximately 130 million individuals over 12 years are infected with HSV-1. Approximately one third of the patients with HSV-1 infection will experience recurrent episodes of herpes labialis.
Most people acquire HSV-1 asymptomatically. Primary infection usually occurs in childhood. It is usually asymptomatic, but may present in different forms: transient gingivostomatitis, pharyngitis or other lesions in and the oral cavity, sometimes with fever.
HSV infects mucous membranes, replicates at the cutaneous entry site (cells of the epidermis and dermis) and may infect the sensory nerve ending that innervate cells at the initial infection site provided that the number of virions is sufficient. The virus is then transported to the sensory nerve nuclei, the trigeminal ganglion for herpes labialis, and remains in a latent state in sensory neurons for the life of the host cell. HSV reactivation could occur in a fraction of population harbouring the latent virus. Upon reactivation, HSV could disseminate throughout the axon from infected cells to the mucosa. Hence, as HSV remains in the mammalian body, orofacial herpes is a recurrent disease. That means that, following reactivation of latent HSV, patients undergo many occurrences of herpes labialis throughout their life. A main challenge for current herpes labialis treatment is to lower the frequency, duration, and severity of these occurrences. The reservoir site of persistent HSV, from the primary infection until reactivation and in between recurrences was found to be in the dorsal roots of the trigeminal ganglion or in the sensory root ganglion. However, the triggering of the viral genome in the ganglion does not exclusively explain the recurrences of herpes labialis. Other sites can be infected with HSV. It was suggested in the state of the art that HSV may well be occult in epithelial cells. Hence, mucous and skin cells might also act as a preferential site for latent HSV (Zakay-Rones Z., Microbiologica, 1986).
Moreover, the viral load in saliva during herpes labialis occurrences increases the persistence of HSV. Indeed, high concentrations of virions in saliva lead to reinfestations through the mucous membranes of the mouth. Such infections further supply the HSV reservoir and thus the latency of HSV.
Up to now no herpes labialis treatment acts on the reservoir of latent HSV.
Reactivation may be triggered by several factors that are specific to the patient, i.e., emotional stress, fever, exposure to ultraviolet light, menses, premenstrual tension, surgical (such as dental or neural) procedures, lip tattooing, dermabrasion or oral traumas. Immune suppression also favours reactivation.
The clinical manifestations of herpes labialis infection depend largely on the anatomic site of infection, immune status of the host and the antigenic type of virus. Most lesions occur on the lips. However, lesions can also occur on the nose, cheeks, or chin. Lesions occurring in the oral cavity or face are less common. Intra-oral lesions are hard to locate and are difficult to distinguish from apthous ulcers, oropharyngeal candidiasis or cancer sores.
In the immunocompetent population, occurrence of herpes labialis follows a predictable course (schematized in FIG. 1), called episodes. An episode of herpes labialis comprises:                Prodrome: episodes of herpes labialis begin with a prodromal stage, during which patients experience pain, burning, itching, tingling, or discomfort in the area of the lesion. It is thus the patient's first indication that herpes labialis is developing. The prodromal stage reliably predicts the onset of lesion outbreak.        Erythema: erythema, a redness of the skin may be present but does not always appear in every patient.        Papula: progression to lesion outbreak is rapid. Clinical manifestations of the lesion are papules (small, solid, inflammatory elevations of the skin that does not contain pus) or indurations of the skin.        Vesicle: within the next 12 hours, lesions of maximal severity, known as cold sores or fever blisters appear on the vermillion border of the lip as multiple, fluid filled vesicles that tend to rupture rapidly and to become confluent into an ulcer in 72-96 hours. The lesion area and pain are generally maximum within 24 hours. This is also the stage at which a cold sore is most contagious.        The first cold sores or fever blisters are named primary vesicles (or primary vesicular lesions). Sometimes, patients present secondary vesicles (or secondary vesicular lesions) which are other cold sores or fever blisters appearing after and around the first vesicles.        Crust: then, the ulcer progresses to a crusting stage. In those areas where the cold sore lesion is not kept wet by moisture from the mouth the ulcer will become dry and scab over with a brownish crust. The formation of this scabbing is often accompanied by an itching or burning sensation. Often the scab will crack or break, which in turn produces bleeding. As time progresses so will the cold sore's healing.        Erythema: during the healing erythema, a redness of the skin may be present but does not always appear in every patient.        Healing/normal skin: the cold sore resolves itself fully, usually without scarring.        
Herpes labialis typically resolves spontaneously within about 7-14 days. Although most of the episodes are mild, some may be severe or disfiguring, causing psychological distress and physical discomfort.
On average, 25% of all episodes do not progress beyond the papule stage. These are called “aborted” (or “abortive” or “non vesicular”) episodes. About one-half of these do not progress beyond the prodromal stage.
Patients may undergo recurrent episodes throughout their life. That means that they have to manage several herpes labialis occurrences throughout their life. The infection is transmitted when the virus is present. The amount of virus is highest within the first eight hours of lesion development and diminishes as the lesions mature. Herpes labialis is spread through saliva or through the direct contact of skin or mucus membranes with lesions or oral secretions of an infected person. Risk of transmission often increases in day care settings due to the large numbers of children who are in close proximity to each other. Most of the transmission in these settings is believed to be asymptomatic. Transmission in households is believed to be from kissing, though it is good to avoid sharing cups, eating utensils, wash cloths, etc. when one has a visible sore.
In HIV patients, herpes labialis appears as chronic, hyperproliferative plaques different from the classic acute mucocutaneous ulcerative lesions and may be related to resistant isolates.
Historically, the difficulty in treating herpes labialis has been attributed to the rapid development of lesions, natural history of viral infection and a strong secondary immunological response that limits lesion duration in untreated patients.
Viral replication is most active before prodromal symptoms or in the first 8 hours after their occurrence and a window of opportunity for antiviral agents may exist when adequate concentrations are used and treatment is initiated during the time that viral replication dominates temporarily the host immune response. Consequently, early high dose antiviral therapy is a logical treatment strategy and ultrashort, minute, treatments have currently been assessed, as described below
Currently, the only compounds recommended as the first line treatment of HSV diseases belong to the class of nucleoside analogues, competitive inhibitor of viral DNA polymerase. Acyclovir and penciclovir are current active principles used in the herpes labialis treatment. Acyclovir has been shown to be the most potent antiviral drug to treat herpes infection.
Several different formulations of acyclovir have been developed for the treatment or prevention of herpes infections: acyclovir 200 mg tablets, 5% acyclovir cream or acyclovir suspension for perfusion. Systemic bioavailability of the drug following administration via oral or topical routes is far from being optimal. The oral absorption of acyclovir is low and highly variable, leading to a poor bioavailability ranging from 15 to 30%. The percutaneous absorption of the 5% acyclovir cream is even poorer with limited transfer of the compound through the mucosa and the skin. The perfusion use is restricted to systemic infections occurring in immunocompromised patients.
In immunocompetent patients, a treatment regimen of acyclovir is 200 mg oral tablets, 5 times daily for 5 days. This treatment showed reduction of time for the loss of the crust (Raborn, J. Am. Dent. Assoc, 1987). However, acyclovir treatment is frequently prolonged due to its incomplete effect. Furthermore, studies have shown that this treatment had no effect on the duration of pain or the time to recovery (Raborn, Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 1997).
Spruance et al. evaluated a regimen of 400 mg of oral acyclovir 5 times daily for 5 days (Spruance, J. Infect. Dis. 1990). Overall in this study, acyclovir reduces the pain and the time of lesion healing. However, a strong inconvenient of these two treatments is their incompliance for patient who have to take these tablets 5 times daily for 5 days.
In frequently recurrent herpes labialis (more than 5 occurrences per year), prophylactic treatment with acyclovir tablets is recommended (Rooney, Annals of Internal Medicine, 2004). Such treatment is, however, very inconvenient for patient since they have to take acyclovir tablets of 400 mg twice daily for 4 months. Currently, the only known prophylactic treatment of frequently recurrent herpes labialis is regular administration of antiviral tablet for a prolonged period of time (4 to 6 months).
The need for a drug with improved pharmacokinetic profile and clinical efficacy led to the development of valacyclovir (L-valine ester of acyclovir), a prodrug of acyclovir with increased bioavailability (absolute bioavailability of acyclovir following oral administration of valacyclovir: 54%). Valacyclovir is administrated via oral route (for instance Valtrex®: containing 500 mg or 1000 mg of valacyclovir hydrochloride or Zeliterx®: containing 500 mg of valaciclovir Chlorhydrate) Likewise, famciclovir, a prodrug of pencyclovir—(diacetyl ester of 6-deoxy pencyclovir, the oral form of penciclovir with an absolute bioavailability of pencyclovir following oral administration of famciclovir of 77%) has been developed and registered for the early treatment of labial herpes. Recently, oral 4 g valacyclovir in 2 divided doses of valacyclovir (Valtrex® 2 g twice daily for one day) (Spotswood L. Journal of Antimicrobial Chemotherapy, 2004) and 1.5 g famciclovir are administered within the first hour following prodromal symptoms of herpes labialis. These two treatments were efficient with high systemic doses administered early on for a short duration therapy. These treatments have been shown to induce a reduction of time to lesion healing versus placebo.
To summarize, valacyclovir or famciclovir-based are oral treatments applied one or two times per day with high dosages (1.5 g or 4 g). These treatments show different drawbacks. Indeed, although reducing time to lesion healing, they do not prevent vesicular lesion and do not allow alleviation of rapid pain and other symptoms. Furthermore, side effect, and notably headaches (in about 10% of treated patients) and/or nausea, are frequently reported, irrespective of the dosage and duration of treatment (Spruance, Antimicrob Agents Chemother 2003).
Topical treatments, such as ointments, are often the preferred option. Indeed, they allow an increased concentration of the active principle at the replication site and/or lesion sites. Presently, for patients developing orofacial herpes (1 to 5 episodes yearly), acyclovir or penciclovir creams or ointments are largely used due to their availability as over-the-counter or preparations without prescription in several countries. This also allows avoiding delays to obtain the mandatory prescriptions, which are required for oral acyclovir and valacyclovir. Although acyclovir in the cream or ointment vehicle had some effect in making cold sore lesions heal more quickly, it was not able to prevent cold sore lesions from arising, even when applied at the prodromal stage. The phenomenon of treatment-induced prevention of lesions is also referred to as “aborted lesions” and represents the holy grail of herpes simplex treatment (Spruance, Antimicrob. Agents Chemother. 2002). Such creams or ointments seem to be more active at the vesicular stage, because of easier transfer through the vesicular membrane or moisterizing properties. Several studies investigated the effects of acyclovir cream. However, none of them reported a decrease in the duration or severity of pain according to consensus (Opsteltel, Can Fam Physician 2008). Furthermore, the topical treatments demonstrated limited efficacy and required multiple applications over several days (Spruance, Herpes, 2002). Some studies have suggested that this limited efficacy is the result of inadequate penetration of the drug in the basal epidermis (Parry, J. Invest Dermatol, 1992). Finally, topical treatments are also incompliant for patients. For instance, patients have to apply topical penciclovir 1% cream every 2 hours during waking hours for 4 days or topical acyclovir 5% cream 5 times daily for 5 days.
International patent application WO2009/115510 relates to topical compositions comprising acyclovir, penciclovir and/or omaciclovir as the active principle. Conveniently, treatment with the composition of the invention is commenced as soon as the first sign of a herpes reoccurrence is detected, such as a tingling of the oral lesion or other manifestation of the prodromal stage. Advantageously the treatment results in an aborted lesion. It needs to be applied five times daily and continued for five days.
Again, the recommended 5 daily applications for 5 days raises the issue of patient compliance. Furthermore, topical treatments have poor effects on pain and could generate local irritation.
Therefore, there is a need for another treatment and/or prevention for herpes labialis which also allows compliance for the patient, reduces global symptoms and/or is well tolerated.
Except for the oral (tablet or capsule) or the topical (cream or ointment) route, no other route of administration has been explored to improve bioavailability of acyclovir and/or increase the concentration at replication sites and/or lesion sites.
Therefore, it is an object of the present invention to fulfil said needs with a composition suitable to mucosal delivery of acyclovir and notably a labial and orofacial delivery.
Therefore it is also an object of the present invention to overcome the other deficiencies in the prior art of herpes labialis treatment.